The skeletal dysplasias are a heterogeneous group of disorders which result in disproportionate short stature and/or skeletal deformities. This Program Project is directed toward a multidisciplinary investigation into the clinical, genetic, morphologic, biochemical and molecular characteristics of skeletal dysplasias. The specific aims of this proposal are: (1) Expansion of the International Skeletal Dysplasia Registry. (2) Definition of the clinical and radiographic variability and genetic heterogeneity of the skeletal dysplasias and elucidation of the natural history, growth characteristics and complications of each of these disorders. (3) Improvement of methods for their prenatal diagnosis. (4) Elucidation of the histological, histochemical, immunohistological and ultrastructural characteristics of chondroosseous tissue in each of the skeletal dysplasias. (5) Identification of the disease genes in osteochondrodysplasias of unknown etiology. (6) Utilization of our human fetal cartilage cDNA library to find novel cartilage-specific cDNA clones. (7) Correlation of the clinical, radiographic and morphological features of each skeletal dysplasia with their specific biochemical and molecular defects. (8) Creation of a new mouse mutagenesis core to generate mouse models carrying null mutants or "knock-in" mutants for each project within the Program Project (9) Definition of how mutations in genes encoding matrix proteins manifest at the molecular level in defective cartilage tissue in osteochondrodysplasias, (10) Elucidation of the role of the Wnt/Lmx1b/sFrp2 pathway in joint formation using mouse models. (11) Elucidation of the pathogenetic mechanism through which each of the mutations identified in man and mouse result in the specific skeletal dysplasia phenotype. This Program Project is divided into two core facilities, the International Skeletal Dysplasia Registry and a Mouse Mutagenesis Core, plus four separate grant proposals: (1) Clinical, morphological and molecular studies; (2) Matrix biochemistry in the skeletal dysplasias; (3) Molecular studies in the skeletal dysplasias; and (4) Developmental studies in the skeletal dysplasias.